CB-839 Demonstrates Encouraging Activity in Combination With Cabozantinib, Everolimus in mRCC

The first-in-class glutaminase inhibitor CB-839 showed encouraging activity and tolerability when combined with everolimus and cabozantinib in heavily pretreated patients with metastatic renal cell carcinoma, according to results from a phase I study presented in a poster session at the 2018 Genitourinary Cancers Symposium in San Francisco, California.

The first-in-class glutaminase inhibitor CB-839 showed encouraging activity and tolerability when combined with everolimus (Afinitor) and cabozantinib (Cabometyx) in heavily pretreated patients with metastatic renal cell carcinoma (mRCC), according to results from a phase I study presented in a poster session at the 2018 Genitourinary Cancers Symposium in San Francisco, California.

CB-839, which is being developed by Calithera Biosciences, Inc, is a potent, selective, reversible and orally bioavailable inhibitor of glutaminase, a pathway that is upregulated in kidney cancer. CB-839’s onco-metabolism activity takes advantage of the unique metabolic requirements of tumor cells and cancer-fighting immune cells such as cytotoxic T-cells. It is currently being evaluated in phase II clinical trials in multiple tumor types in combination with standard-of-care agents.

The open-label study was conducted in 2 parts. Part 1 was a dose-escalation study which enrolled patients with locally advanced, metastatic and/or refractory solid tumors who received CB-839 capsules orally 2 or 3 times daily.

Part 2 enrolled patients with triple-negative breast cancer (TNBC), non—small cell lung cancer (NSCLC), RCC, mesothelioma, fumarate hydratase-deficient tumors, succinate dehydrogenase (SDH)–deficient gastrointestinal stromal tumors (GIST), SDH-deficient non-GIST tumors, tumors harboring mutations in isocitrate dehydrogenase-1 (IDH1) orIDH2, and tumors harboring amplifications in c-MYC.

As an extension of parts 1 and 2, patients were treated with CB-839 in combination with chemotherapy. Patients with locally advanced or metastatic TNBC were treated with paclitaxel and CB-839, patients with advanced clear cell RCC or papillary RCC were treated with everolimus in combination with CB-839, patients with advanced NSCLC lacking theEGFRT790M mutation were treated with erlotinib (Tarceva) and CB-839, patients with NSCLC harboringKRASmutations were treated with docetaxel and CB-839, and patients with histologically confirmed diagnosis of locally advanced, inoperable, or metastatic RCC treated with cabozantinib in combination with CB-839.

Findings of 12 patients with mRCC treated with CB-839 and everolimus who were evaluable for response by the data cutoff were presented in a poster by Nizar M. Tannir, MD, of The University of Texas MD Anderson Cancer Center, et al. Of the evaluable patients, 10 had clear cell RCC, and 2 had papillary disease. Some degree of tumor shrinkage and disease control was experienced by each patient, including 4 patients who had a partial response (PR) and 8 patients who had stable disease (SD). In the clear cell patient population, the disease control rate was 100% and the response rate was 40%.

Findings were also presented of 24 evaluable patients who received the combination of CB-839 and everolimus. The disease control rate was 92%, including 1 patient with a PR and 21 patients with SD. The median progression-free survival (PFS) was 5.8 months.

A total of 27 patients were enrolled in the CB-839/everolimus (n = 17) and expansion (n = 10) cohorts (7 at 400 mg/kg dosage, 13 at 600 mg/kg, 7 at 800 mg/kg) and 11 patients (9 with clear cell histology and 2 with papillary) were enrolled in the CB-839/cabozantinib escalation cohorts.

Eligibility criteria included mRCC with clear cell or papillary histology, an ECOG performance status of 0 or 1, and RECIST measurable disease. Patients with clear cell histology were required to have received prior treatment with at least 1 anti-VEGF therapy.

Patients were administered CB-839 in oral doses that ranged from 600 to 800 mg twice a day (6 at 600 mg/kg, 5 at 800 mg/kg) in combination with fixed standard oral doses of cabozantinib and everolimus.

Patients in the CB-839/everolimus group had a median of 2 prior lines of therapy, including 64% of clear cell patients who had received ≥2 prior anti-VEGF therapies. Patients in the CB-839/cabozantinib group had a median of 3 prior therapies (range, 0-6), including tyrosine kinase inhibitors, mTOR inhibitors, and checkpoint inhibitors. A maximum-tolerated dose was not reached; 800 mg/kg was selected as the recommended phase II dose for CB-839.

The most common treated-related adverse events of grade 3 or greater were fatigue (11%), anemia, hyperglycemia, and neutropenia (7% each) for CB-839/everolimus (n = 27), and diarrhea (14%) and platelet count decrease (14%), including 1 dose-limiting toxicity at 600 mg, for CB-839/cabozantinib (n = 7).

Based on this efficacy and safety data, Calithera Biosciences, Inc. has initiated the randomized phase II ENTRATA trial of CB-839 in combination with everolimus in later-stage patients. The trial is currently enrolling and is expected to enroll approximately 65 patients.

The company also plans to initiate the CANTATA trial, a phase II randomized, placebo-controlled trial in approximately 300 patients with clear-cell RCC who have previously received 1 or 2 prior lines of therapy. The trial is expected to begin in the second quarter of 2018.